Carbon substituted aminothiazole inhibitors of cyclin dependent kinases

ABSTRACT

Compounds of the formula  
                 
 
     and pharmaceutically acceptable salts thereof. As used in formula I, and throughout the specification, the symbols have the following meanings:  
     R 1 ═R 2 , COR 3 , CONH 2 , CONR 2 R 3 , COOR 2 , or SO 2 R 2 ;  
     R 2 =alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl;  
     R 3 ═H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl;  
                 
 
     , where n=0,1,2; m=1,2 but both n and m cannot be 2, or  
     , where i, j=0 or 1 but cannot both be 1, and Y=optionally substituted alkene, alkyne, or any 2 adjacent carbon atoms of a cycloalkyl or cycloheteroalkyl ring of 3-7 atoms;  
     R 4 =alkyl with two or more carbon atoms, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or R 9  with the proviso that when R 1  is acetyl or propionyl and Y=alkene, then R 4  cannot be nitrofuryl or 2-quinolinyl;  
     R 5 , R 6 , R 7 , R 8 =independently H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, halo, or hydroxy, alkoxy, amino, NR 12 R 13 , thio, or alkylthio with the proviso that only one such heteroatom group is bonded to any one carbon atom; R 9 = 
                 
 
      where Z═O, NR 14 , S;  
     R 10 , R 11 =independently H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, halo, hydroxy, alkoxy, alkylcarbonyloxy, carboxy, alkyloxycarbonyl, amino, NR 15 R 16 , carbamoyl, ureido, thio, or alkylthio;  
     R 12 , R 13 , R 14 , R 15 , R 16 =independently H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl.  
     The compounds of formula I are protein kinase inhibitors and are useful in the treatment of proliferative diseases, for example, cancer, inflammation and arthritis. They may also be useful in the treatment of Alzheimer&#39;s disease, and cardiovascular disease.

[0001] This application claims priority benefit under Title 35 §119(e) of United States Provisional Application No. 60/089,747, filed Jun. 18, 1998, and entitled Carbon Substituted Aminothiazole Inhibitors of Cyclin Dependent Kinases, the entire contents of which are incorporated herein by reference.

BRIEF DESCRIPTION OF THE INVENTION

[0002] The present invention is directed to compounds of the formula

[0003] and pharmaceutically acceptable salts thereof. As used in formula I, and throughout the specification, the symbols have the following meanings:

[0004] R¹═R², COR³, CONH₂, CONR²R³, COOR², or SO₂R²;

[0005] R²=alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl;

[0006] R³═H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl;

[0007] , where n=0,1,2; m=1,2 but both n and m cannot be 2, or

[0008] , where i, j=0 or 1 but cannot both be 1, and Y=optionally substituted alkene, alkyne, or any 2 adjacent carbon atoms of a cycloalkyl or cycloheteroalkyl ring of 3-7 atoms;

[0009] R⁴=alkyl with two or more carbon atoms, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or R⁹, with the proviso that when R¹ is acetyl or propionyl and Y=alkene, then R⁴ cannot be nitrofuryl or 2-quinolinyl;

[0010] R⁵, R⁶, R⁷, R⁸=independently H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, halo, or hydroxy, alkoxy, amino, NR¹²R¹³, thio, or alkylthio, with the proviso that only one such heteroatom group is bonded to any one carbon atom;

[0011] where Z═O, NR¹⁴, S;

[0012] R¹⁰, R¹¹=independently H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, halo, hydroxy, alkoxy, alkylcarbonyloxy, carboxy, alkyloxycarbonyl, amino, NR¹⁵R¹⁶, carbamoyl, ureido, thio, or alkylthio;

[0013] R¹², R¹³, R¹⁴, R¹⁵, R¹⁶=independently H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl.

[0014] The compounds of formula I are protein kinase inhibitors and are useful in the treatment of proliferative diseases, for example, cancer, inflammation and arthritis. They may also be useful in the treatment of Alzheimer's disease, and cardiovascular disease.

DESCRIPTION OF THE INVENTION

[0015] The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds, and for methods of using such compounds.

[0016] Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.

[0017] It should be noted that any heteroatom with unsatisfied valances is assumed to have the hydrogen atom to satisfy the valances.

[0018] Carboxylate anion refers to a negatively charged group —COO⁻.

[0019] The term “alkyl” or “alk” refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 12 carbon atoms unless otherwise defined. An alkyl group is an optionally substituted straight, branched or cyclic saturated hydrocarbon group. When substituted, alkyl groups may be substituted with up to four substituent groups, R as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with “branched alkyl group”. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. Exemplary substituents may include but are not limited to one or more of the following groups: halo (such as F, Cl, Br, I), haloalkyl (such as CCl₃ or CF₃), alkoxy, alkylthio, hydroxy, carboxy (—COOH), alkyloxycarbonyl (—COOR), alkylcarbonyloxy (—OCOR), amino (—NH₂), carbamoyl (—NHCOOR— or —OCONHR—), urea (—NHCONHR—), amidinyl (—CNHNHR or —CNRNH₂), or thiol (—SH). Alkyl groups as defined may also comprise one or more carbon to carbon double bonds or one or more carbon to carbon triple bonds.

[0020] The term “alkenyl” refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 12 carbon atoms and at least one carbon to carbon double bond.

[0021] The term “alkynyl” refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond.

[0022] Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings. Exemplary unsubstituted such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Exemplary substituents include one or more of the following groups: halogen, alkyl, alkoxy, alkyl hydroxy, amino, nitro, cyano, thiol and/or alkylthio.

[0023] The terms “alkoxy” or “alkylthio”, as used herein, denote an alkyl group as described above bonded through an oxygen linkage (—O—) or a sulfur linkage (—S—), respectively.

[0024] Sulfoxide and sulfone denote groups bonded by —SO— or —SO₂— linkages, respectively.

[0025] The term “alkyloxycarbonyl”, as used herein, denotes an alkoxy group bonded through a carbonyl group. An alkoxycarbonyl radical is represented by the formula: —C(O)OR, where the R group is a straight or branched C₁₋₆ alkyl group.

[0026] The term “alkylcarbonyl” refers to an alkyl group bonded through a carbonyl group.

[0027] The term “alkylcarbonyloxy”, as used herein, denotes an alkylcarbonyl group which is bonded through an oxygen linkage.

[0028] The term “arylalkyl”, as used herein, denotes an aromatic ring bonded to an alkyl group as described above.

[0029] The term “aryl” refers to monocyclic or bicyclic aromatic rings, e.g. phenyl, substituted phenyl and the like, as well as groups which are fused, e.g., napthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. Aryl groups may optionally be substituted with one or more groups including, but not limited to halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl S(O)_(m) (m=, 0,1, 2), or thiol.

[0030] The term “heteroaryl” refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S, or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Exemplary heteroaryl groups include the following: thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrrolidinyl, piperidinyl, thiazolyl, oxazolyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl, tetrazolyl, pyridazinyl, pyrimidinal, triazinylazepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, benzofurazanyl and tetrahydropyranyl. Exemplary substituents include one or more of the following: halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, trifluoromethyl, cycloalkyl, nitro, cyano, amino, alkylS(O)_(m) (m=, 0,1, 2), or thiol.

[0031] The term “heteroarylium” refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge.

[0032] The term “heterocycloalkyl” refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by said heteroatoms.

[0033] The term “quaternary nitrogen” refers to a tetravalent positively charged nitrogen atom including, e.g. the positively charged nitrogen in a tetraalkylammonium group (e.g. tetramethylammonium, N-methylpyridinium), the positively charged nitrogen in protonated ammonium species (e.g. trimethylhydroammonium, N-hydropyridinium), the positively charged nitrogen in amine N-oxides (e.g. N-methyl-morpholine-N-oxide, pyridine -N-oxide), and the positively charged nitrogen in an N-amino-ammonium group (e.g. N-aminopyridinium).

[0034] The term “heteroatom” means O, S or N, selected on an independent basis.

[0035] The term “halogen” or “halo” refers to chlorine, bromine, fluorine or iodine.

[0036] When a functional group is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene, T. W. et al., Protective Groups in Organic Synthesis, Wiley, N.Y. (1991).

[0037] Suitable examples of salts of the compounds according to the invention with inorganic or organic acids are hydrochloride, hydrobromide, sulfate, phosphate. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included.

[0038] All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The definition of the compounds according to the invention embraces all possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

[0039] All configurational isomers of compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds of the present invention very particularly embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cycloalkyl or heterocycloalkyl rings.

[0040] It should be understood that solvates (e.g. hydrates) of the compounds of formula I are also within the scope of the present invention. Methods of salvation are generally known in the art. Accordingly, the compounds of the instant invention may be in the free or hydrate form, and may be obtained by methods exemplified by the following schemes.

[0041] The synthesis of compounds of formula I can proceed through the known aldehyde of formula II (Scheme 1) which was prepared according to the procedures set forth in II Farmaco 44, 1011, (1989) and the references therein. Treatment of II with either (R²CO)₂O or R¹—L, where L is a leaving group such as a halogen or sulfonate ester, yields compounds of formula III. Condensation of formula III with phosphorus-stabilized anions such as the phosphonate of formula IV or a Wittig reagent in the presence of base yields compounds of formula V (that is, compounds of formula I where A contains an alkene present as either the cis or trans isomer). Alternatively, compounds of formula V may be prepared by first reacting formula II with the phosphonate of formula IV or a Wittig reagent in the presence of base, and then treating the resulting product with (R²CO)₂O or R¹—L.

[0042] Compounds of formula V may be converted into other compounds of formula I as shown in Scheme 2. For example, treatment of compounds of formula V with agents such as H₂ on Pd/C yields the saturated compounds of formula VI (which is a compound of formula I. Alternatively compounds of formula V may be epoxidized with agents such as dimethyldioxirane or m-chloroperbenzoic acid to yield epoxides of formula VII (which are compounds of formula I where Y=the carbon atoms of oxirane). Cyclopropanation of the olefin with agents such as ZnCuCH₂ or diazomethane may yield cyclopropanes of formula VIII (which are compounds of formula I where Y=cyclopropane).

[0043] Aldehydes of formula III may also be converted into compounds of formula I which have R⁷ or R⁸ groups containing oxygen (Scheme 3). For example, addition of organometallic reagents of formula R*-M, where R*═R⁴(R⁵R⁶C)_(i)— or R⁴(R⁵R⁶C)_(I)—Y— and M=a metal, would yield compounds of formula IX (that is, compounds of formula I where R⁷=hydroxy and R⁸═H). Alkylation of the hydroxyl group in compounds of formula IX using W—L, where W=alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, and L is a leaving group such as a halogen or sulfonate ester, would yield ethers of formula X (that is, compounds of formula I with R⁷=alkoxy).

[0044] Scheme 4 outlines a procedure that may be used for the solid phase synthesis of compounds of formula I. A benzyl chloride resin, such as that depicted by formula XII, may be alkylated by an aminothiazole of formula III (where R¹═CF₃CO) to give a compound of formula XII. Coupling with phosphorus stabilized anions such as compounds of formula IV will yield alkenes of formula XIII which may be deprotected by a reducing agent such as sodium borohydride, or a base such as sodium hydroxide, to give amines of formula XIV. The amines of formula XIV may react with R¹—L or (R²CO)₂O to give compounds of formula XV, which may be cleaved from the resin with trifluoroacetic acid to give compounds of formula V (which are compounds of formula I where Y is an alkene). Compounds of formula IX or X may also be synthesized on solid phase using analogous chemistry to that shown in Scheme 3 by starting with aldehyde XII.

[0045] Compounds of formula I wherein R⁴═R⁹ may be synthesized from aldehydes of formula III (Scheme 5). These aldehydes may be reduced with agents such as sodium borohydride to give alcohols of formula XVI which may be converted into a compound of formula XVII, where L is a leaving group such as a halogen or sulfonate ester, by treatment with agents such as p-toluenesulfonyl chloride and base or thionyl chloride. The anion of dialkylmalonate esters of formula XVIII may be alkylated by compounds of formula XVII to form diesters of formula XIX, where W=alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl. These diesters may be saponified and decarboxylated to form acids of formula XX which may be coupled with amines of formula XXI to give amides of formula XXII. These amides may be cyclized upon exposure to dehydrating agents such as POCl₃ to form compounds of formula VI which are compounds of formula I where Z═O.

[0046] Compounds of formula I wherein R4=R9 and Y=alkynyl or Z-alkenyl may be prepared from halomethyl oxazoles such as XXIII (Scheme 6). Displacement of the chlorine to give the acetate XXIV, followed by basic hydrolysis and oxidation provides a 2-oxazolyl aldehyde XXVI. The aldehyde may be treated with a reagent such as carbon tetrabromide and triphenylphosphine to give a dibromo olefin XXVII. Elimination of HBr by strong base, followed by lithiation and quenching the acetylenic anion with tributyltin chloride gives an acetylenic stannane XXVIII, which may be coupled with a 2-iodo aminothiazole XXIX, to give XXX, which is a compound of formula I wherein R⁴═R⁹ and Y is alkynyl. The acetylenic compounds of formula XXX may be hydrogenated to provide cis olefins XXXI and XXXIII, which are compounds of formula I wherein R⁴═R⁹ and Y is Z-alkenyl.

[0047] Compounds of formula I wherein R1=R2 may be prepared by the methods shown in Scheme 7. 5-Formyl-2-aminothiazole II is reacted with a nitrosating agent such as tBuONO and CuBr2 to form the 2-bromo derivative XXXIV. Following procedures as described in Scheme I, the aldehyde is reacted with a phosphonate of formula IV or a Wittig reagent in the presence of base to provide an olefin of formula XXXV. Reaction of the 2-bromo olefin of formula XXXV with a compound of formula R2NH2 in the presence of a base such as sodium hydride gives compounds of formula, which is a compound of formula I wherein R1=R2 and Y is alkenyl.

[0048] Alternatively, compounds of formula XXXVI where R¹═R² and Y is alkenyl may be prepared according to Scheme 8. The amino group of compound II may be protected with a reagent such as di-t-butyl dicarbonate to give XXXVII, followed by reaction with a phosphonate of formula IV or a Wittig reagent in the presence of base such as an alkoxide or sodium hydride to give a compound of formula XXXVIII. Treatment of XXXVIII with R²L where L is a leaving group such as halo or sulfonate, in the presence of base, followed by removal of the protecting group gives a compound of formula XXXVI, which is a compound of formula I where R¹═R² and Y is alkenyl.

[0049] Compounds of formula R⁴CH₂P(O)(OEt)₂ may be prepared from compounds of formula R⁴CH₂L, where L is a leaving group such as halogen or sulfonate ester, by heating with triethylphosphite. Compounds of formula R⁹-L, where Z═O, may be prepared from LCH₂CN and R¹¹C(N₂)COR¹⁰, according to part E of Example 2.

[0050] The starting compounds of Schemes 1-7 are commercially available or may be prepared by methods known to one of ordinary skill in the art.

[0051] All compounds of formula I may be prepared by modification of the procedures described herein.

[0052] Preferred compounds of formula I are those where:

[0053] R¹═R², COR³, or CONR²R³;

[0054] R²═alkyl, aryl, or heteroaryl;

[0055] R³═H, alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;

[0056] , where n=0, 1, 2; m=1, 2, or

[0057] , where i, j=0 or 1 but cannot both be 1, and Y=optionally substituted alkene, alkyne, or any two adjacent carbon atoms of a cycloalkyl ring;

[0058] R⁴=alkyl with two or more carbon atoms, aryl, heteroaryl, or R⁹;

[0059] R⁵, R⁶, R⁷, R⁸=independently H, or alkyl;

[0060] where Z═O;

[0061] R¹⁰, R¹¹=independently H, or alkyl.

[0062] The compounds according to the invention have pharmacological properties; in particular, the compounds of formula I are inhibitors of protein kinases such as the cyclin dependent kinases (cdks), for example, cdc2 (cdk1), cdk2, and cdk4. The novel compounds of formula I are expected to be useful in the therapy of proliferative diseases such as cancer, inflammation, arthritis, Alzheimer's disease and cardiovascular disease. These compounds may also be useful in the treatment of topical and systemic fungal infections.

[0063] More specifically, the compounds of formula I are useful in the treatment of a variety of cancers, including (but not limited to) the following:

[0064] carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin;

[0065] hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukemia, B-cell lymphoma, and Burkett's lymphoma;

[0066] hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia;

[0067] tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and

[0068] other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, neuroblastoma and glioma.

[0069] Due to the key role of cdks in the regulation of cellular proliferation in general, inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, angiogenesis, and endotoxic shock.

[0070] Compounds of formula I may also be useful in the treatment of Alzheimer's disease, as suggested by the recent finding that cdk5 is involved in the phosphorylation of tau protein (J. Biochem, 117, 741-749 (1995)).

[0071] Compounds of formula I may also act as inhibitors of other protein kinases, e.g., protein kinase C, her2, rafl, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, Pl3 kinase, wee1 kinase, Src, Abl, and thus be effective in the treatment of diseases associated with other protein kinases.

[0072] The compounds of this invention may also be useful in combination with known anti-cancer treatments such as radiation therapy or with cytostatic and cytotoxic agents, such as for example, but not limited to, DNA interactive agents, such as cisplatin or doxorubicin; inhibitors of farnesyl protein transferase, such as those described in pending U.S. application Ser. No. 08/802,239 which was filed on Feb. 20, 1997; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors, such as CPT-11 or topotecan; tubulin stabilizing agents, such as paclitaxel, docetaxel or the epothilones; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; and antimetabolites, such as methoxtrexate; antiangiogenic agents, such as angiostatin; and kinase inhibitors, such as her2 specific antibodies.

[0073] If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. For example, the cdc2 inhibitor olomucine has been found to act synergistically with known cytotoxic agents in inducing apoptosis (J. Cell Sci., 108, 2897 (1995)). Compounds of formula I may be used sequentially with known anti-cancer or cytotoxic agents when a combination formulation is inappropriate.

[0074] cdc2/cyclin B1 Kinase Assay

[0075] cdc2/cyclin B1 kinase activity was determined by monitoring the incorporation of ³²P into histone HI. The reaction consisted of 50 ng baculovirus expressed GST-cdc2, 75 ng baculovirus expressed GST-cyclin B1, 1 μg histone HI (Boehringer Mannheim), 0.2 μCi of ³²P γ-ATP and 25 μM ATP in kinase buffer (50 mM Tris, pH 8.0, 10 mM MgCl₂, 1 mM EGTA, 0.5 mM DWF). The reaction was incubated at 30° C. for 30 minutes and then stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration of 15% and incubated on ice for 20 minutes. The reaction was harvested onto GF/C unifilter plates (Packard) using a Packard Filtermate Universal harvester, and the filters were counted on a Packard TopCount 96-well liquid scintillation counter (Marshak, D. R., Vanderberg, M. T., Bae, Y. S., Yu, I. J., J. of Cellular Biochemistry, 45, 391-400 (1991), incorporated by reference herein).

[0076] cdk2/cyclin E Kinase Assay

[0077] cdk2/cyclin E kinase activity was determined by monitoring the incorporation of ³²P into the retinoblastoma protein. The reaction consisted of 2.5 ng baculovirus expressed GST-cdk2/cyclin E, 500 ng bacterially produced GST-retinoblastoma protein (aa 776-928), 0.2 μCi ³²P γ-ATP and 25 μM ATP in kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl₂, 5 mM EGTA, 2 mM DTT). The reaction was incubated at 30° C. for 30 minutes and then stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration of 15% and incubated on ice for 20 minutes. The reaction was harvested onto GF/C unifilter plates (Packard) using a Packard Filtermate Universal harvester, and the filters were counted on a Packard TopCount 96-well liquid scintillation counter.

[0078] cdk 4/cyclin D1 Kinase Activity

[0079] cdk4/cyclin D1 kinase activity was determined by monitoring the incorporation of ³²P in to the retinoblastoma protein. The reaction consisted of 165 ng baculovirus expressed as GST-cdk4, 282 ng bacterially expressed as S-tag cyclin D1, 500 ng bacterially produced GST-retinoblastoma protein (aa 776-928), 0.2 μCi ³²P γ-ATP and 25 μM ATP in kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl₂, 5 mM EGTA, 2 mM DTT). The reaction was incubated at 30° C. for 1 hour and then stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration of 15% and incubated on ice for 20 minutes. The reaction was harvested onto GF/C unifilter plates (Packard) using a Packard Filtermate Universal harvester, and the filters were counted on a Packard TopCount 96-well liquid scintillation counter (Coleman, K. G., Wautlet, B. S., Morissey, D, Mulheron, J. G., Sedman, S., Brinkley, P., Price, S., Wedster, K. R. (1997) Identification of CDK4 Sequences involved in cyclin D, and p16 binding. J. Biol. Chem. 272,30:18869-18874, incorporated by reference herein).

[0080] The following examples and preparations describe the manner and process of making and using the invention and are illustrative rather than limiting. It should be understood that there may be other embodiments which fall within the spirit and scope of the invention as defined by the claims appended hereto.

EXAMPLE 1

[0081]

A. Preparation of 2-acetamido-5-bromothiazole

[0082] To a solution of 2-amino-5-bromothiazole (22.3 g, 85.9 mmol) in methylene chloride (100 mL) and pyridine (60 mL) was added acetic anhydride (11 mL) slowly with stirring. The mixture was allowed to stir for 2.5 hours, warmed to room temperature, and stirred for an additional 4 hours. Most of the solvent was removed in vacuo and the residue was washed with ethyl acetate and aqueous HCl. The organic solution was then washed with water, dried over MgSO₄ and concentrated to give a crude solid. This solid was triturated with Et₂O, filtered, washed with Et₂O, and dried to give 2-acetamido-5-bromothiazole as a solid (15.1 g, 80%, C₅H₅BrN₂OS, MS m/e 222 (M+H)⁺).

B. Preparation of ethyl 3-((E)-2-acetamido-thiazol-5-yl)-acrylate

[0083] A mixture of acetamido-5-bromothiazole (440 mg, 2.0 mmol), ethyl acrylate (400 mg, 4 mmol) and triethylamine (3 mL) in DMF (3 mL) was stirred at 90° C. under argon in the presence of Pd(tol₃P)₂Cl₂ (150.0 mg) for 24 h. The mixture was concentrated and the residue was dissolved in methylene chloride (100 mL), washed with water and dried over MgSO₄. The solution was concentrated and the residue was purified by column chromatography (SiO₂, CH₂Cl₂:MeOH/100:5) to afford ethyl 3-((E)-2-acetamido-thiazol-5-yl)-acrylate (100 mg, 21%) as a solid (m.p. 239-240° C., C₁₀H₁₂N₂O₃S, MS m/e 240.9 (M+H)⁺).

EXAMPLE 2

[0084]

A. Preparation of 2-amino-thiazol-5-ylcarboxaldehyde

[0085] 2-Amino-thiazol-5-ylcarboxaldehyde was synthesized according to the procedure set forth in II Farmaco 44, 1011, (1989) and the references therein.

B. Preparation of 2-acetamido-thiazol-5-ylcarboxaldehyde

[0086] To a suspension of 2-amino-thiazol-5-ylcarboxaldehyde (5.0 g, 39 mmol) in toluene (500 mL) was added acetic anhydride (11.0 mL, 117 mmol). The mixture was heated to 110° C. for 5 hours. Upon cooling to room temperature, a solid precipitated out of the solution. The reaction mixture was concentrated under vacuum to give 2-acetamido-thiazol-5-ylcarboxaldehyde as a light brown colored solid (6.5 g, 98%, C₆H₆N₂O₂S, MS m/e 171 (M+H)⁺).

C. Preparation of Diazomethane

[0087] Caution: diazomethane is potentially explosive. Care should be taken to use plastic containers, or glassware free of scratches. Solid KOH (60 g) was dissolved in water to make 150 mL of a 40% KOH solution. This solution was cooled at 0° C. and ether (500 mL) was added. To this cooled mixture was added 1-methyl-3-nitro-1-nitrosoguanidine (50 g, 0.34 mol) in portions over 45 minutes. After addition was complete, the ether layer was decanted and to give a solution of diazomethane which was used directly.

D. Preparation of 1-diazo-3,3-dimethyl-2-butanone

[0088] To the diazomethane solution was added a solution of trimethylacetyl chloride (15 mL, 0.12 mol) in ether (100 mL) dropwise over 40 minutes. After addition was complete, the solution was allowed to warm slowly overnight to room temperature. The solution was purged with a flow of nitrogen gas to remove any excess diazomethane and the resulting solution was concentrated to give 1-diazo-3,3-dimethyl-2-butanone as a yellow oil which was used directly in the next step.

E. Preparation of 2-(chloromethyl)-5-t-butyloxazole

[0089] To a stirred solution of chloroacetonitrile (40 mL) and boron trifluoride etherate (20 mL, 0.16 mmol) at 0° C. was added 1-diazo-3,3-dimethyl-2-butanone in chloroacetonitrile (40 mL) dropwise over a period of 20 minutes. After addition was complete, the mixture was stirred at 0° C. for one hour and then partitioned between saturated NaHCO₃, solution (700 mL) and CH₂Cl₂ (500 mL). The aqueous solution was extracted with CH₂Cl₂ (500 mL) and the combined organic layers were washed with brine (400 mL) and dried over MgSO₄. After filtration, the solution was concentrated and then distilled under vacuum using an oil bath temperature of 40° C. The 2-(chloromethyl)-5-t-butyloxazole (9.2 g, 44% overall from the acid chloride, C₈H₁₂ClNO, MS m/e 174 (M+H)⁺) was obtained as a light yellow oil.

F. Preparation of (5-t-butyl-oxazol-2-ylmethyl)-phosphonic acid diethyl ester

[0090] A solution of 2-(chloromethyl)-5-t-butyloxazole (8.00 g, 46.1 mmol) in triethylphosphite (15.3 g, 92.0 mmol) was heated at 120° C. for 18 hours. After cooling the mixture to room temperature, toluene (30 mL) was added and the solution was concentrated in vacuo with a bath temperature of 70° C. This procedure was repeated three times and the resulting brown oil was dried in vacuo at 90° C. for 30 minutes to give (5-t-butyl-oxazol-2-ylmethyl)-phosphonic acid diethyl ester (12.4 g, 98%, C₁₂H₂₂NO₄P, MS m/e 276 (M+H)⁺) as a red-orange liquid.

G. Preparation of N-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-acetamide

[0091] To a solution of (5-butyl-oxazol-2-ylmethyl)-phosphonic acid diethyl ester (195 mg, 0.708 mmol) in tetrahydrofuran (10 mL) was added potassium t-butoxide (2.2 mL, 1 M in THF) via syringe. After 10 minutes, a solution of 2-acetamido-thiazo-5-ylcarboxaldehyde (100 mg, 0.587 mmol) in THF (6 mL) was added via syringe. Over the course of a half-hour, a precipitate formed in the solution. Methanol (1.5 mL) was added to dissolve the precipitate, and after an additional half-hour, the reaction was concentrated under reduced pressure to form a slurry. This was diluted with CHCl₃ (50 mL) and quenched with water (25 mL). The solution was extracted with CHCl₃ (3×50 mL) and ethyl acetate (3×50 mL) until all the formed solid was in solution. The combined organic layers were washed with water (50 mL) and dried over brine followed by MgSO₄ and then concentrated to give a yellow solid. The crude solid was purified by chromatography (SiO₂, 5% MeOH/CHCl₃) to afford N-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-acetamide (118 mg, 69%, m.p. 275° C., C₁₄H₁₇N₃O₂S, MS m/e 292 (M+H)⁺) as a light yellow solid. HPLC-HI 100% at 3.95 min (YMC S5 ODS coulm 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

EXAMPLE 3

[0092]

A. Preparation of N-[5-(2-(5-t-butyl-oxazol-2-yl)-ethyl)-thiazol-2-yl]-acetamide

[0093] A solution N-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]acetamide (67 mg, 0.23 mmol) in ethyl acetate (10 mL) was added to a suspension of pre-reduced Pd/C (10%) in ethyl acetate (5 mL). The reaction flask was fitted with a hydrogen balloon and stirred for 24 hours. The reaction was filtered, and the mixture was resubmitted to hydrogenation using the same conditions as above. After an additional 24 hours, the reaction was filtered through a plug of celite, concentrated, and purified by chromatography (SiO₂, 5% MeOH/CHCl₃) to give N-[5-(2-(5-t-butyl-oxazol-2-yl)-ethyl)-thiazol-2-yl]-acetamide as a white solid (3.5 mg, 5%, C₁₄H₁₉N₃O₂S, MS m/e 294 (M+H)⁺). HPLC-HI 91% at 6.75 min (Zorbax SB C18 column 4.6×75 mm, 10-90% aqueous methanol over 8 minutes containing 0.1% TFA, 2.5 mL/min, monitoring at 220 nm).

EXAMPLE 4

[0094]

A. Preparation of [(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-carbamic acid t-butyl ester

[0095] A sample of [(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-carbamic acid t-butyl ester could be prepared according to the methods described in Example 2.

B. Preparation of 2-amino-5-[(E)-2-(5-t-butyl-oxazol-2-yl)-vinyl]-thiazole

[0096] To a suspension of [5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazo-2-yl]-carbamic acid t-butyl ester (1.5 g, 4.3 mmol) in tetrahydrofuran (30 mL) and water (3 mL) was added concentrated HCl (3 mL) dropwise. After addition was complete, the mixture was heated at 60° C. overnight. The solution was concentrated in vacuo to give a slurry, which was neutralized with saturated aqueous NaHCO₃ solution. The resulting solid was filtered and washed with water and dried to give the free base (732 mg, 68%, C₁₂H₁₅N₃OS, MS m/e 250 (M+H)⁺).

C. Preparation of N-[5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-phenylacetamide

[0097] To a solution of 2-amino-5-[(E)-2-(5-t-butyl-oxazol-2-yl)-vinyl]-thiazole (20 mg, 0.08 mmol) in dry CH₂Cl₂ (1 mL) was added dry DMF (0.1 mL) and N,N-diisopropylethylamine (28 μL, 0.16 mmol). The resulting solution was cooled to 0° C. and phenyl acetyl chloride (21 μL, 0.16 mmol) was added via syringe. The reaction mixture was allowed to warm to room temperature over two hours and then concentrated. Chromatography (SiO₂, 5% MeOH/CH₂Cl₂) provided a N-[5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-phenylacetamide as a mixture of Z and E isomers which were separated by reverse-phase HPLC to give the Z isomer (3 mg, 10%, MS m/e 368 (M+H)⁺) as a light yellow solid, and the E isomer (3 mg, 10%, C₂₀H₂₁N₃O₂S, MS m/e 368 (M+H)⁺) as a yellow solid. (Z)-isomer: HPLC-HI 86% at 4.05 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 254 nm). (E)-isomer: HPLC-HI 84% at 4.18 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 254 nm).

EXAMPLE 5

[0098]

A. Preparation of 2-hydroxymethyl-5-t-butyloxazole

[0099] To a mixture of 2-chloromethyl-5-t-butyloxazole (13.0 g, 75.1 mmole), Cs₂CO₃ (36.0 g, 110.5 mmole) and acetic acid (10.5 mL, 192.6 mmole) in acetonitrile (120 ml) was heated at 65 deg C. overnight. All the solvent was removed under reduced pressure, the residue was partitioned between water (60 mL) and EtOAc (100 mL) and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined EtOAc solution was dried over MgSO₄ and concentrated to an oil.

[0100] The oil was dissolved in methanol (30 mL) and added with a solution of NaOH (6.50 g, 163 mmole) in 30 ml of water, and stirred at room temperature overnight. MeOH was removed under reduced pressure, and the aqueous layer was extracted with EtOAc (3×80 mL). The combined EtOAc solution was dried over MgSO₄ and concentrated to give 2-hydroxymethyl-5-t-butyloxazole as oil (11.76 g, 100%).

B. Preparation of 1,1-dibromo-2-(5′-t-butyloxazol-2-yl)ethylene

[0101] To a stirred solution of oxalyl chloride (45 mL, 90 mmole) at −78 deg C. under argon was added dropwise dimethyl sulfoxide (8.80 mL, 124 mmole). The reaction mixture was stirred at −78 deg C. for 10 min., and was treated with a solution of 2-hydroxymethyl-5-t-butyloxazole (11.7 g, 75.1 mmole) in anhydrous methylene chloride (30 mL) over 20 min. The mixture was stirred at this temperature for 1 hour, then triethylamine was added slowly (31.0 mL, 222 mmole), during which the reaction mixture became a yellowish slurry. After stirring at −78 deg C. for 20 min, the reaction mixture was warmed to room temperature, added with methylene chloride (100 mL) and stirred for 1 hour. The solid was filtered off and washed with EtOAc. The filtrate was washed with 5% aqueous citric acid (100 mL) and brine (50 mL), dried over MgSO₄. Concentration and column chromatography (silica gel, EtOAc/hexane 1:4) afforded 2-formyl-5-t-butyloxazole as a light yellow oil (10.1 g).

[0102] To a stirred solution of carbon tetrabromide (24.0 g, 72.4 mmole) in methylene chloride (200 mL) at 5-10 deg C. under argon atmosphere was added triphenylphosphine (37.0 g, 141 mmole) in portions. The reaction mixture was stirred for 5 min and treated with a solution of 2-formyl-5-t-butyloxazole in methylene chloride (60 mL). The reaction mixture was stirred at room temperature for 2 hours, while a white solid precipitated out of the solution. The solid was filtered off, the filtrate concentrated and purified (silica gel, EtOAc/hexane 1:4) to give 1,1-dibromo-2-(5-t-butyl-oxazol-2-yl)ethylene as a pale solid (9.13 g, 39 %).

C. Preparation of N-[5-(2-(5-t-butyl-oxazol-2-yl)-acetelenyl)-thiazol-2-yl]-acetamide

[0103] To a stirred solution of 1,1-dibromo-2-(5-t-butyl-oxazol-2-yl)ethylene (6.0 g, 19 mmole) in anhydrous THF (80 mL) at −78 deg C. under argon atmosphere. was added with 1.6 M n-butyllithium (32 mL, 51 mmole) in hexane dropwise over 20 min., the reaction mixture, stirred at −78 deg C. for 30 min and treated with tributyltin chloride (5.5 mL, 20 mmole). The reaction mixture was stirred for 30 min, warmed to 0 deg C., stirred at 0 deg C. for 30 min, and then at room temperature for 45 min. The mixture was passed through a short column of silica gel (deactivated with 2% triethylamine in hexane), and eluted with 10% EtOAc in dichloromethane to obtain crude product of 1-tributylstannyl-2-(5-t-butyl-oxazol-2-yl)acetylene as a brown oil (9.10 g).

[0104] To a stirred solution of above crude product of tin compound under argon and 2-N-acetylamino-5-iodothiazole (4.65 g, 17.3 mmole) in anhydrous THF (100 mL) at room temperature was added solid tris(dibenzylideneacetone)dipalladium(0) (1.40 g, 1.53 mmole), followed by trifurylphosphine (2.0 g, 8.6 mmole). The reaction mixture was stirred at room temperature for 10 min., then heated at 65 deg C. for 2.5 hours. The catalyst was filtered off, the filtrate concentrated and purified by column silica gel chromatography (EtOAc/hexane 1:2 to 2:1) to give N-[5-(2-(5-t-butyl-oxazol-2-yl)-ethynyl)-thiazol-2-yl]-acetamide as a light brown solid (2.60 g, 46%). C14H15N3O2S, MS m/e 290 (M+H)+. HPLC-HI 100% at 4.02 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

EXAMPLE 6

[0105]

Preparation of N-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-aminopyridine

[0106] To a solution of 2-aminopyridine (238 mg, 2.56 mmol) in THF (8 mL) under argon was added sodium hydride (100 mg of 60% oil dispersion, 2.5 mmol) and the reaction stirred at 60 deg C. for 15 minutes, cooled to room temperature and 2-bromo-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazole] (200 mg, 0.64 mmol) was added in one portion. The reaction mixture was stirred for 20 minutes, quenched with hydrochloric acid, washed with water and extracted with ethyl acetate. The organic layers were separated and concentrated to give a crude product which was heated with ethyl acetate: hexanes (1:1), cooled, filtered, and dried under vacuum to give the desired product. C₁₇H₁₈N₄OS, MS m/e 327 (M+H)⁺. HPLC-HI 100% at 4.24 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

[0107] Using the procedures described herein or by modification of the procedures described herein as known to one or ordinary skill in the art, the following additional compounds have been prepared: TABLE 1 Pro- cedure Ex- MS of am- Molecular (M + Ex- ple Structure Formula H)⁺ ample 7

C₁₀H₁₄N₂O₃S 243 3 8

C₁₄H₁₇N₃O₂S 292 2 9

C₁₆H₂₁N₃O₃S 336 2 10

C₁₈H₁₈N₄O₂S 355 4 11

C₁₃H₁₅N₃O₂S 278 4 12

C₁₉H₁₈F₂N₄O₂S 405 4 13

C₁₉H₁₈F₂N₄O₂S 405 4 14

C₁₉H₂₀N₄O₂S 369 4 15

C₁₉H₂₀N₄O₂S 369 4 16

C₂₄H₂₃N₃O₂S 419 4 17

C₂₄H₂₃N₃O₂S 419 4 18

C₂₀H₂₁N₃O₂S 368 4 19

C₂₀H₂₁N₃O₂S 368 4 20

C₁₁H₁₆N₆OS 281 3 21

C₁₄H₁₄N₂OS 259 2 22

C₁₃H₁₂N₂OS 245 2 23

C₁₇H₂₀N₂OS 301 2 24

C₁₃H₁₁ClN₂OS 280 2 25

C₁₃H₁₄BrN₃O₂S 357 2 26

C₁₃H₁₃N₃O₂S 276 5 27

C₁₃H₁₄N₂OS 247 3 28

C₁₆H₁₈N₂OS 287 2 29

C₁₆H₂₀N₂OS 289 3 30

C₁₂H₁₁N₃OS 246 2 31

C₁₂H₁₈N₆OS 295 3 32

C₁₃H₁₂N₂OS 245 4 33

C₁₂H₁₁N₃OS 246 4 34

C₁₈H₁₆F₂N₄O₂S 391 4 35

C₁₆H₂₁N₃O₂S 320 4 36

C₉H₁₀N₂O₃S 227 2 37

C₁₉H₂₂N₄O₂S 371 3 38

C₁₂H₁₁N₃OS 246 2 39

C₁₂H₁₁N₃OS 246 2 40

C₁₂H₁₁N₃OS 246 2 41

C₁₂H₁₁N₃OS 246 2 42

C₂₃H₃₃N₅O₄S 477 4 43

C₁₉H₂₇N₅O₂S 391 4 44

C₁₈H₂₄N₄O₃S 377 4 45

C₁₅H₂₁N₃O₂S 308 3 46

C₁₅H₁₇N₃O₂S 304 5 47

C₁₄H₁₆FN₃O₂S 310 2 48

C₁₇H₁₉N₅O₂S 358 4 49

C₁₈H₂₅N₅O₂S 377 4 50

C₂₂H₂₃N₃O₅S 443 4 51

C₂₀H₂₈N₄O₃S 406 4 52

C₁₄H₁₂N₄OS 285 53

C₁₆H₁₃N₃O₂S 312 2 54

C₁₆H₂₃N₃OS 306 6 55

C₂₀H₂₃N₃OS 354 6 56

C₁₉H₂₆N₄O₂S 376 4 57

C₂₀H₂₁N₅O₃S 412 4 58

C₂₄H₂₉N₅O₂S 453 4 59

C₂₀H₂₀N₄O₄S 413 4 60

C₁₉H₂₀N₄O₃S 385 4 61

C₂₀H₂₀Cl₂N₄O₃S 468 4 62

C₁₈H₁₉N₅O₂S 370 4 63

C₁₉H₂₀N₄O₃S 385 4 64

C₂₀H₂₁N₅O₃S 412 4 65

C₁₉H₂₀N₄O₃S 385 4 66

C₂₁H₂₃N₅O₃S 427 4 67

C₂₄H₂₉N₅O₄S 485 4 68

C₂₂H₂₅N₅O₃S 441 4 69

C₂₂H₂₆N₆O₃S 456 4 70

C₂₅H₂₉N₅O₅S 513 4 71

C₁₈H₁₉N₅O₂S 370 4 72

C₂₀H₂₈N₄O₂S 390 4 73

C₁₈H₂₄N₄O₃S 377 4 74

C₂₀H₂₈N₄O₃S 406 4 75

C₁₉H₂₆N₄O₂S 376 4 76

C₂₀H₂₈N₄O₂S 390 4 77

C₂₀H₂₉N₅O₂S 405 4 78

C₁₇H₂₂N₄O₃S 363 4 79

C₁₈H₂₅N₅O₂S 377 4 80

C₁₉H₂₆N₄O₃S 392 4 81

C₂₀H₂₈N₄O₃S 406 4 82

C₂₀H₂₀N₄O₄S 413 4 83

C₁₉H₂₅N₅O₃S 405 4 84

C₁₈H₁₉N₅O₂S 370 4 85

C₂₁H₂₁N₃O₅S 428 4 86

C₂₀H₁₉N₅O₅S₂ 475 4 87

C₁₉H₂₆N₄O₃S 392 4 88

C₁₉H₁₉ClN₄O₃S 420 4 89

C₂₄H₃₀N₆O₂S 468 4 90

C₂₀H₂₂N₄O₂S 383 4 91

C₁₇H₁₈N₆O₄S 403 4 92

C₂₁H₂₀N₆O₄S 454 4 93

C₁₉H₂₆N₄O₃S 392 4 94

C₂₂H₃₀N₄O₄S 448 4 95

C₂₀H₂₆N₄O₄S 420 4 96

C₁₉H₂₄N₄O₄S 405 4 97

C₁₉H₁₇F₃N₄O₂S 423 4 98

C₁₉H₂₆N₄O₂S 376 4 99

C₂₀H₁₉N₅O₂S 394 4 100

C₁₈H₁₈ClN₅O₂S 405 4 101

C₁₇H₂₅N₃O₃S 352 3 102

C₁₅H₁₉N₃O₂S 306 Scheme 2 103

C₁₄H₁₉N₃O₃S 310 Scheme 3 104

C₁₈H₂₀N₄OS 341 6 105

C₁₉H₁₉F₃N₄O₂S 425 3 106

C₁₉H₁₉N₅O₄S 414 4 107

C₁₉H₂₀N₆O₃S 413 4 108

C₁₅H₁₉N₃O₂S 306 Scheme 2 109

C₁₅H₁₉N₃O₃S 322 4 110

C₂₀H₂₈N₄O₂S 390 4 111

C₂₆H₃₄N₄O₃S 484 4 112

C₁₉H₁₉N₃O₂S 354 4 113

C₁₈H₁₇Cl₂N₅O₂S 439 4 114

C₁₉H₁₆F₂N₄O₂S 403 5 115

C₁₄H₁₇N₃O₃S 308 6 116

C₁₄H₁₈N₄O₂S 307 6 117

C₁₅H₂₁N₃O₂S 308 6 118

C₁₄H₁₆F₃N₃OS 332 6 119

C₁₃H₁₅N₃O₂S 278 4 120

C₁₇H₂₂N₄O₄S 379 4 121

C₁₈H₂₆N₆O₂S 392 4 122

C₂₀H₂₉N₅O₂S 405 4 123

C₁₈H₂₅N₃O₃S 364 6 124

C₁₅H₁₉N₃O₃S 322 6 125

C₁₄H₁₆N₄OS 289 6 126

C₁₇H₁₉N₅O₂S 358 4 127

C₁₈H₁₉N₃OS 326 6 128

C₁₈H₂₁N₅O₂S 372 4 129

C₂₀H₂₄N₆O₃S 430 4 130

C₂₃H₂₅N₅O₂S 437 4 131

C₂₄H₃₂N₆O₄S 502 4 132

C₁₈H₂₂N₆O₂S 387 4 133

C₁₉H₂₄N₆O₂S 402 4 134

C₁₉H₂₄N₆O₂S 402 4 135

C₁₄H₁₉N₃O₂S 294 6 136

C₁₆H₂₃N₃O₂S 322 6 137

C₁₆H₂₃N₃O₂S 322 6 138

C₁₇H₂₅N₃O₂S 336 6 139

C₁₅H₂₁N₃O₂S 308 6 140

C₁₉H₃₀N₄OS 364 6 141

C₁₈H₂₂N₆O₃S 403 6 142

C₁₇H₂₃N₃O₃S 350 4 143

C₂₀H₂₃N₃OS 354 6 144

C₁₉H₂₁N₃OS 340 6 145

C₁₈H₁₈ClN₃OS 361 6 146

C₁₉H₂₁N₃O₂S 356 6 147

C₁₇H₁₈N₄OS 327 6 148

C₁₉H₂₇N₅O₂S 391 4 149

C₁₆H₁₇N₅OS 328 6 150

C₁₇H₁₈N₄OS 327 6 151

C₁₈H₁₈ClN₃OS 361 6 152

C₂₀H₂₂N₄O₂S 383 4 153

C₁₇H₁₉N₅O₂S 358 4 154

C₂₀H₂₁N₃O₂S 368 4 155

C₁₆H₂₁N₃O₂S 320 4 156

C₁₆H₁₇N₅OS 328 6 157

C₁₉H₁₈F₂N₄O₂S 405 4 158

C₁₉H₂₀N₄O₃S 385 4 159

C₁₉H₂₁N₃O₂S 356 6 160

C₁₉H₂₁N₃O₂S 356 6 161

C₂₁H₂₀N₄OS 377 6 162

C₁₆H₁₇N₅OS 328 6 163

C₂₃H₂₉N₅OS 425 6 164

C₁₇H₁₈N₄O₂S 343 6 165

C₁₈H₂₀N₄OS 341 6 166

C₁₇H₁₈N₄O₂S 343 6 167

C₂₆H₃₂N₆O₃S 510 4 168

C₂₀H₂₂N₄O₂S 383 4 169

C₂₅H₃₁N₅O₃S 483 4 170

C₂₆H₃₂N₄O₃S 482 4 171

C₁₆H₁₇N₅OS 328 6 172

C₂₁H₂₄N₄O₂S 398 4 173

C₁₇H₁₉N₅OS 342 6 174

C₁₅H₁₉N₃OS 290 6 175

C₂₀H₂₃N₄O₂S 385 4 176

C₁₆H₁₉N₃O₂S 318 5 177

C₂₀H₁₉N₃O₂S 366 5 178

C₁₇H₁₇N₅O₂S 356 5 179

C₁₇H₁₉N₅O₂S 358 4 180

C₁₇H₁₇Cl₂N₅O₂S 427 4 181

C₁₉H₁₇N₇O₂S 408 4 182

C₁₈H₂₁N₅O₂S 372 4 183

C₁₇H₁₆N₄OS 325 5 184

C₁₇H₁₈N₄OS 327 6 185

C₁₅H₁₃N₃S 268 6 186

C₁₇H₁₉N₅O₂S 358 6 187

C₁₉H₂₁N₃O₂S 356 6 188

C₁₈H₂₀N₄OS 341 6 189

C₁₈H₂₀N₄OS 341 6 

We claim:
 1. A compound of the formula:

and pharmaceutically acceptable salts thereof wherein: R¹═R², COR³, CONH₂, CONR²R³, COOR², or SO₂R²; R²=alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl; R³═H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl;

, where n=0,1,2; m=1,2 but both n and m cannot be 2, or , where i, j=0 or 1 but cannot both be 1, and Y=optionally substituted alkene, alkyne, or any 2 adjacent carbon atoms of a cycloalkyl or cycloheteroalkyl ring of 3-7 atoms; R⁴=alkyl with two or more carbon atoms, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or R⁹ with the proviso that when R¹ is acetyl or propionyl and Y=alkene, then R⁴ cannot be nitrofuryl or 2-quinolinyl; R⁵, R⁶, R⁷, R⁸=independently H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, halo, or hydroxy, alkoxy, amino, NR¹²R¹³, thio, or alkylthio with the proviso that only one such heteroatom group is bonded to any one carbon atom;

where Z═O, NR¹⁴, S; R¹⁰, R¹¹=independently H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, halo, hydroxy, alkoxy, alkylcarbonyloxy, carboxy, alkyloxycarbonyl, amino, NR¹⁵R¹⁶, carbamoyl, ureido, thio, or alkylthio; R¹², R¹³, R¹⁴, R¹⁵, R¹⁶=independently H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl.
 2. The compound as recited in claim 1, wherein R¹═R², COR³, or CONR²R³; R²=alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R³=H, alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;

, where n=0, 1, 2; m=1, 2, or , where i, j=0 or 1 but cannot both be 1, and Y=optionally substituted alkene, alkyne, or any two adjacent carbon atoms of a cycloalkyl ring; R⁴=alkyl with two or more carbon atoms, aryl, heteroaryl, or R⁹ with the proviso that when R¹ is acetyl or propionyl and Y=alkene, then R⁴ cannot be nitrofuryl or 2-quinolinyl; R⁵, R⁶, R⁷, R⁸=independently H, or alkyl;

where Z═O; R¹⁰, R¹¹=independently H, alkyl or cycloalkyl.
 3. The compound as recited in claim 1, wherein: R¹═COR³; R³═H, alkyl, heteroaryl, arylalkyl, or heteroarylalkyl;

, where n=0,1; m=1, or , where i, j=0 or 1 but cannot both be 1, and Y=an optionally substituted alkene; R⁴═R⁹; R⁵, R⁶, R⁷, R₈=independently H, or alkyl.

where Z═O; and R¹⁰, R¹¹=independently H, alkyl or cycloalkyl.
 4. The compound as recited in claim 1, wherein: R¹═COR³; R³=alkyl, arylalkyl, heteroaryl, or heteroarylalkyl;

where n=0,1; m=1; R⁵, R⁶, R⁷, R⁸=independently H, or alkyl; R⁴═R⁹;

where Z═O; R¹⁰=alkyl or cycloalkyl, and R¹¹═H.
 5. The compound as recited in claim 1, wherein: R¹═COR³; R³=alkyl, arylalkyl, heteroaryl, or heteroarylalkyl;

, where i, j=0 or 1 but cannot both be 1, and Y=an optionally substituted alkene or alkyne; R⁴═R⁹; R⁵, R⁶, R⁷, R⁸=independently H, or alkyl;

where Z═O; R¹⁰=alkyl or cycloalkyl,; and R¹¹═H.
 6. The compound as recited in claim 1, wherein: R¹═COR³; R³=alkyl, arylalkyl, heteroaryl, or heteroarylalkyl;

, where n=0,1; m=1, or , where i, j=0 or 1 but cannot both be 1, and Y=an optionally substituted alkene; R⁴=alkyl with two or more carbon atoms, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl with the proviso that when R¹ is acetyl or propionyl and Y=alkene, then R⁴ cannot be nitrofuryl or 2-quinolinyl; R⁵, R⁶, R⁷, R⁸=independently H, or alkyl.
 7. The compound as recited in claim 1, wherein: R¹═R²; R²=alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;

, where n=0,1; m=1, or , where i, j=0 or 1 but cannot both be 1, and Y=an optionally substituted alkene; R⁴═R⁹; R⁵, R⁶, R⁷, R⁸=independently H, or alkyl.

where Z═O; and R¹⁰, R¹¹=in dependently H, alkyl or cycloalkyl.
 8. The compound as recited in claim 1, wherein: R¹═R²; R²=alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;

where n=0,1; m=1; R⁵, R⁶, R⁷, R⁸=independently H, or alkyl; R⁴═R⁹;

where Z═O; R¹⁰=alkyl or cycloalkyl,; and R¹¹═H.
 9. The compound as recited in claim 1, wherein: R¹═R²; R²=alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;

, where i, j=0 or 1 but cannot both be 1, and Y=an optionally substituted alkene or alkyne; R⁴═R⁹; R⁵, R⁶, R₇, R⁸=independently H, or alkyl;

where Z═O; R¹⁰=alkyl or cycloalkyl,; and R¹¹═H.
 10. The compound as recited in claim 1, wherein: R¹═R²; R²=alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;

, where n=0,1; m=1, or, , where i, j=0 or 1 but cannot both be 1, and Y=an optionally substituted alkene; R⁴=alkyl with two or more carbon atoms, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R⁵, R⁶, R⁷, R⁸=independently H, or alkyl.
 11. The compound as recited in claim 1, wherein: R¹═CONR²R³; R²=alkyl, heteroaryl, arylalkyl, or heteroarylalkyl; R³═H, alkyl, heteroaryl, arylalkyl, or heteroarylalkyl;

, where n=0,1; m=1, or , where i, j=0 or 1 but cannot both be 1, and Y=an optionally substituted alkene; R⁴═R⁹; R⁵, R⁶, R⁷, R⁸=independently H, or alkyl;

where Z═O; and R¹⁰, R¹¹=independently H, alkyl or cycloalkyl.
 12. The compound as recited in claim 1, wherein: R¹═CONR²R³; R²=alkyl, arylalkyl, heteroaryl, or heteroarylalkyl; R³=H, alkyl, heteroaryl, arylalkyl, or heteroarylalkyl;

where n=0,1; m=1; R⁴═R⁹; R⁵, R⁶, R⁷, R⁸=independently H, or alkyl;

where Z═O; R¹⁰=alkyl or cycloalkyl; and R¹¹═H.
 13. The compound as recited in claim 1, wherein: R¹═CONR²R³; R²=alkyl, arylalkyl, heteroaryl, or heteroarylalkyl; R³=H, alkyl, heteroaryl, arylalkyl, or heteroarylalkyl;

, where i, j=0 or 1 but cannot both be 1, and Y=an optionally substituted alkene or alkyne; R⁴═R⁹; R⁵, R⁶, R⁷, R⁸=independently H, or alkyl;

where Z═O; R¹⁰=alkyl or cycloalkyl, and R¹¹═H.
 14. The compound as recited in claim 1, wherein: R¹═CONR²R³; R²=alkyl, arylalkyl, heteroaryl, or heteroarylalkyl; R³═H, alkyl, heteroaryl, arylalkyl, or heteroarylalkyl;

, where n=0,1; m=1, or, , where i, j=0 or 1 but cannot both be 1, and Y=an optionally substituted alkene; R⁴=alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R⁵, R⁶, R⁷, R⁸=independently H, or alkyl.
 15. A compound selected from the group consisting of: Ethyl 3-((E)-2-acetamido-thiazol-5-yl)-acrylate; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-acetamide; N-[5-(2-(5-t-Butyl-oxazol-2-yl)-ethyl)-thiazol-2-yl]-acetamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-phenylacetamide; N-[5-(2-(5-t-Butyl-oxazol-2-yl)-ethynyl)-thiazol-2-yl]-acetamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-aminopyridine; Ethyl 3-(2-acetamido-thiazol-5-yl)-propionate; N-[(Z)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-acetamide; [(E)-5-(2-(5-Isopropyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-carbamic acid t-butyl ester; N-[(E)-5-(2-(5-Isopropyl-oxazol -2-yl)-vinyl)-thiazol-2-yl]-2-pyridin-3-yl-acetamide; N-[(E)-5-(2-(5-Isopropyl-oxazol -2-yl)-vinyl)-thiazol-2-yl]-acetamide; 1-(2,6-Difluorophenyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(2,6-Difluorophenyl)-3-[(Z)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; N-[(Z)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-pyridin-3-yl-acetamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-pyridin-3-yl-acetamide; N-[(Z)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-naphthalen-2-yl-acetamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-naphthalen-2-yl-acetamide; N-[(Z)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-phenylacetamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-phenylacetamide; N-[5-(2-(2-Isopropyl-tetrazol-5-yl)-ethyl)-thiazol-2-yl]-acetamide; N-[(E)-5-(2-(3-Methylphenyl)-vinyl)-thiazol-2-yl]-acetamide; N-[(E)-5-(2-Phenyl)-vinyl)-thiazol-2-yl]-acetamide; N-[(E)-5-(2-(4-t-Butyl-phenyl)-vinyl)-thiazol-2-yl]-acetamide; N-[(E)-5-(2-(3-Chlorophenyl)-vinyl)-thiazol-2-yl]-acetamide; N-[(E)-5-(2-Bromo-2-(5-isopropyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-acetamide; N-[5-(2-(5-Isopropyl-oxazol-2-yl)-ethynyl)-thiazol-2-yl]-acetamide; N-[5-(2-Phenyl)-ethyl)-thiazol-2-yl]-acetamide; N-[(E)-5-(2-(3-Isopropylphenyl)-vinyl)-thiazol-2-yl]-acetamide; N-[5-(2-(3-Isopropylphenyl)-ethyl)-thiazol-2-yl]-acetamide; N-[(E)-5-(2-(3-Pyridinyl)-vinyl)-thiazol-2-yl]-acetamide; N-[5-(2-(2-t-Butyl-tetrazol-5-yl)-ethyl)-thiazol-2-yl]-acetamide; N-[(Z)-5-(2-Phenyl)-vinyl)-thiazol-2-yl]-acetamide; N-[(Z)-5-(2-(3-Pyridinyl)-vinyl)-thiazol-2-yl]-acetamide; 1-(2,6-Difluorophenyl)-3-[(E)-5-(2-(5-isobutyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-isobutyramide; Ethyl 3-((Z)-2-acetamido-thiazol-5-yl)-acrylate; N-[5-(2-(5-t-Butyl-oxazol-2-yl)-ethyl)-thiazol-2-yl]-2-pyridin-3-yl-acetamide; N-[(E)-5-(2-(4-Pyridinyl)-vinyl)-thiazol-2-yl]-acetamide; N-[(E)-5-(2-(2-Pyridinyl)-vinyl)-thiazol-2-yl]-acetamide; N-[(Z)-5-(2-(4-Pyridinyl)-vinyl)-thiazol-2-yl]-acetamide; N-[(Z)-5-(2-(2-Pyridinyl)-vinyl)-thiazol-2-yl]-acetamide; 4-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-ylcarbamoylmethyl]-piperazine-1-carboxylic acid t-butyl ester; 1-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-ylcarbamoylmethyl]-4-methylpiperazine; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-morpholin-4-yl-acetamide; N-[5-(3-(5-t-Butyl-oxazol-2-yl)-propyl)-thiazol-2-yl]-acetamide; N-[5-(3-(5-t-Butyl-oxazol-2-yl)-propynyl)-thiazol-2-yl]-acetamide; N-[(Z)-5-(2-Fluoro-2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-acetamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(3H-imidazol-4-yl)-acetamide; )-acetamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-piperazin-1-yl-acetamide; Methyl 4-N-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-carbamoylmethoxy-benzoate; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(1-methyl-piperidin-4-yloxy)-acetamide; N-[5-(5-Phenyl-3H-imidazol-4-yl)-thiazol-2-yl]-acetamide; N-[(E)-5-(2-(5-phenyloxazol-2-yl)-vinyl)-thiazol-2-yl]-acetamide; Isobutyl-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-amine; [(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-phenethylamine; 1-Cyclohexyl-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(4-Carbamoylphenyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(4-Piperidinylphenyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(Benzo[1,3]dioxol-5-yl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(2-Hydroxyphenyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(2,6-Dichloro-4-methoxyphenyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(2-Pyridinyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(3-Hydroxyphenyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(3-Carbamoylphenyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(4-Hydroxyphenyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(3-Carbamoyl-4-methylphenyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 2-Dimethylamino-ethyl 4-{3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol -2-yl]-ureido}-benzoate; 1-[4-(N,N-Dimethylcarbamoyl)phenyl]-3-[(E)-5-(2-(5-butyl-oxazol-2-yl)-vinyl)-thiazol -2-yl]-urea; 1-(2-Morpholinylpyridin-5-yl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol -2-yl]-urea; Methyl 5-{3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-ureido}-2-N-morpholino-benzoate; 1-(3-Pyridinyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(2-Methylcyclohexyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 4-Hydroxy-piperidine-1-carboxylic acid [(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol -2-yl]-amide; 2-(2-Hydroxyethyl)-piperidine-1-carboxylic acid [(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-amide; 2-Methyl-piperidine-1-carboxylic acid [(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol -2-yl]-amide; 1-Cyclohexyl-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-1-methyl-urea; 3-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-1-methyl-1-(1-methyl-piperidin-4-yl)-urea; 3-Hydroxy-pyrrolidine-1-carboxylic acid [(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol -2-yl]-amide; 4-Methyl-piperazine-1-carboxylic acid [(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-amide 4-Hydroxymethyl-piperidine-1-carboxylic acid [(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-amide; 4-(2-Hydroxyethyl)-piperidine-1-carboxylic acid [(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl )-thiazol-2-yl]-amide; 1-[4-carboxyphenyl]-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; Piperidine-1,4-dicarboxylic acid 4-amide 1-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-amide; 1-(4-Pyridinyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 4-N-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-carbamoylmethoxy-benzoic acid; 6-{3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-ureido}-1,1-dioxo-1,2,3a,7a-tetrahydro-1λ⁶-benzo[d]isothiazol-3-one; 3-Hydroxymethyl-piperidine-1-carboxylic acid [(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-amide; 1-(2-Chloro-4-hydroxyphenyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-[4-(4-Methyl-piperazin-1-yl)phenyl]-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 3-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-1-methyl-1-phenyl-urea; 1-(2,6-Dihydroxy-pyrimidin-4-yl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-3-(2,3-dihydro-phthalazine-1,4-dion-6-yl)-urea; 1-[(1S,2S)-2-Hydroxycyclohexyl]-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; (1R,2S)-2-{3-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-ureido}-cyclohexanecarboxylic acid ethyl ester; (1R,2S)-2-{3-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-ureido}-cyclohexanecarboxylic acid; 1-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-2-fluoro-vinyl)-thiazol-2-yl]carbamoyl-piperidine-4-carboxylic acid; 1-(2,6-Difluorophenyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-2-fluoro-vinyl)-thiazol-2-yl]-urea; 2-Piperidin-4-yl-N-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-acetamide; 1-(4-cyanophenyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(2-Chloro-pyridin-5-yl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; [5-(2-(5-t-Butyl-oxazol-2-yl)-ethyl)-thiazol-2-yl]-carbamic acid t-butyl ester; N-[5-((S)-2-(5-t-Butyl-oxazol-2-yl)-cyclopropyl)-thiazol-2-yl]-acetamide; N-[5-(2-(5-t-Butyl-oxazol-2-yl)-2-hydroxyethyl)-thiazol-2-yl]-acetamide; [(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-pyridin-3-ylmethyl-amine; 1-(2,6-Difluorophenyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-2-fluoro-ethyl)-thiazol-2-yl]-urea; 1-(5-Carboxy-pyridin-2-yl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(5-Carbamoyl-pyridin-2-yl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; N-[5-((R)-2-(5-t-Butyl-oxazol-2-yl)-cyclopropyl)-thiazol-2-yl]-acetamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-(3-hydroxy)-propionamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(N-methylpiperidin-4-yl)-acetamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-((4-(2-diethylamino)ethoxy)phenyl)-acetamide; N-[(E)-5-(2-(5-Isopropyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-phenyl-acetamide; 1-(3,5-Dichloro-pyridin-4-yl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(2,6-Difluorophenyl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-ethynyl)-thiazol-2-yl]-urea; [(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-ylamino)-acetic acid; 2-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-ylamino]-acetamide; 3-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-ylamino]-propan-1-ol; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(2,2,2-trifluoroethyl)-amine; N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-formamide; (3R,4R)-3,4-Dihydroxy-pyrrolidine-1-carboxylic acid [(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-amide; 1-(4-methylpiperizin-1-yl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; 1-(2,6-Dimethylpiperidin-1-yl)-3-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-urea; [(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-ylamino]-acetic acid, t-butyl ester; [(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-ylamino]-acetic acid, methyl ester; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(cyanomethyl)-amine; N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(imidazol-1-yl)-acetamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-aniline; N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(1-methyl-imidazol-4-yl)-acetamide; N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-3[(imidazol-4-yl)]-2-(N′-acetylamino)-propionamide; N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-[3-(1-methyl-benzimidazol-2-yl)]-propionamide; (S)-N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-3[(1-methyl-imidazol-4-yl)]-2-(N-t-butoxyacetylamino)-propionamide; (S)-N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-3[(1-methyl-imidazol-4-yl)]-2-(N-t-butoxyacetylamino)-propionamide; (S)-N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-3-(imidazol-4-yl)-2-amino-propionamide; (S)-N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-3-(1-methyl-imidazol-5-yl)-2-amino-propionamide; (S)-N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-3-(1-methyl-imidazol-4-yl)-2-amino-propionamide; 2-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-ylamino]-ethanol; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(4-hydroxy-butyl)-amine; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-(3-methoxypropyl)-amine; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(3-hydroxy-3-methyl-butyl)-amine; (Z)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(3-hydroxy-propyl)-amine; N′-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-N,N-dimethyl-pentane-1,5-diamine; 6-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-ylamino]-4-propoxy-[1,3,5]triazin-2-ol; [(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-carbamic acid t-butyl ester; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(2,6-dimethylphenyl)-amine; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(2-methylphenyl)-amine; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(4-chlorophenyl)-amine; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(4-methoxyphenyl)-amine; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(pyridyl-3-yl)-amine; 3-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-1-(1-methyl-piperidin-4-yl)-urea; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(pyrazine-2-yl)-amine; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(pyridyl-4-yl)-amine; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(3-chloro-phenyl)-amine; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(2-methylpyridin-3-yl)-acetamide; N-[(Z)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(imidazol-1-yl)-acetamide; N-[(Z)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-phenylacetamide; N-[(Z)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-isobutyramide; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(pyrimidin-2-yl)-amine; 1-[(Z)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-3-(2,6-difluorophenyl)-urea; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(1-oxy-pyridin-3-yl)-acetamide; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(2-methoxyphenyl)-amine; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(3-methoxyphenyl)-amine; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(isoquinolin-3-yl)-amine; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl-(pyrimidin-4-yl)-amine; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine; (E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-(1-oxy-pyridin-2-yl)-amine; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-benzene-1,3-diamine; [(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-(1-oxy-pyridin-4-yl)-amine; 3-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-1-(4-(N-pyrrolidin-1-ylethyl-carbamoyl)phenyl)-urea; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(pyridin-3-yl)-propionamide; 3-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-1-[4-(pyrrolidin-1-ylethoxy)-phenyl]-urea; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-[4-(pyrrolidin-1 -ylethoxy)-phenyl]-acetamide; [(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-pyridazin-3-yl-amine; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(2-methyl-pyridin-3-yl)-propionamide; N-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-pyridine-2,6-diamine; Cyclopropyl-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-amine; 3-(N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-carbamoyl-methyl)-1-methyl-pyridinium iodide; N-[5-(5-t-Butyl-oxazol-2-yl)-ethynyl)-thiazol-2-yl]-isobutyramide; [5-(5-t-Butyl-oxazol-2-yl)-ethynyl)-thiazol-2-yl]-2-phenylacetamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-imidazol-1-yl-acetamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-pyrazol-1-yl-acetamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(4,5-dichloro-imidazol-1-yl)-acetamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(4,5-dicyano-imidazol-1-yl)-acetamide; N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(2-methyl-imidazol-1-yl)-acetamide; [5-(5-t-Butyl-oxazol-2-yl)-ethynyl)-thiazol-2-yl]-(pyridin-2-yl)-amine; [(Z)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-(pyridin-2-yl)-amine; (5-Benzyl-thiazol-2-yl)-pyridin-2-yl-amine; [(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-(6-methoxy-pyrimidin-4-yl)-amine; [(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-(3-hydroxymethyl-phenyl)-amine; [(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-(4-methyl-pyridin-2-yl)-amine; [(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-(6-methyl-pyridin-2-yl)-amine.
 16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
 17. A pharmaceutical composition comprising a compound of claim 1 in combination with pharmaceutically acceptable carrier and an anti-cancer agent formulated as a fixed dose.
 18. A method of inhibiting protein kinases which comprises administering to a mammalian specie in need thereof an effective protein kinase inhibiting amount of a compound of claim
 1. 19. A method of inhibiting cyclin dependent kinases which comprises administering to a mammalian specie in need thereof an effective cyclin dependent kinase inhibiting amount of a compound of claim
 1. 20. A method of inhibiting cdc2 (cdk1) which comprises administering to a mammalian specie in need thereof an effective cdc2 inhibiting amount of a compound of claim
 1. 21. A method of inhibiting cdk2 which comprises administering to a mammalian specie in need thereof an effective cdk2 inhibiting amount of a compound of claim
 1. 22. A method of inhibiting cdk3 which comprises administering to a mammalian specie in need thereof an effective cdk3 inhibiting amount of a compound of claim
 1. 23. A method of inhibiting cdk4 which comprises administering to a mammalian specie in need thereof an effective cdk4 inhibiting amount of a compound of claim
 1. 24. A method of inhibiting cdk5 which comprises administering to a mammalian specie in need thereof an effective cdk5 inhibiting amount of a compound of claim
 1. 25. A method of inhibiting cdk6 which comprises administering to a mammalian specie in need thereof an effective cdk6 inhibiting amount of a compound of claim
 1. 26. A method of inhibiting cdk7 which comprises administering to a mammalian specie in need thereof an effective cdk7 inhibiting amount of a compound of claim
 1. 27. A method of inhibiting cdk8 which comprises administering to a mammalian specie in need thereof an effective cdk8 inhibiting amount of a compound of claim
 1. 28. A method for treating proliferative diseases comprising administering to a mammalian specie in need thereof a therapeutically effective amount of a composition of claim
 17. 29. A method for treating cancer comprising administering to a mammalian specie in need thereof a therapeutically effective amount of a composition of claim
 17. 30. A method for treating inflammation, inflamatory bowel disease, or transplantation rejection, comprising administering to a mammalian specie in need thereof a therapeutically effective amount of a composition of claim
 17. 31. A method for treating arthritis comprising administering to a mammalian specie in need thereof a therapeutically effective amount of a composition of claim
 17. 32. A method for treating proliferative diseases comprising administering to a mammalian specie in need thereof a therapeutically effective amount of a composition of claim
 18. 33. A method for treating cancer comprising administering to a mammalian specie in need thereof a therapeutically effective amount of a composition of claim
 18. 34. A method for treating inflammation, inflammatory bowel disease, or transplantation rejection, comprising administering to a mammalian specie in need thereof a therapeutically effective amount of a composition of claim
 18. 35. A method for treating arthritis comprising administering to a mammalian specie in need thereof a therapeutically effective amount of a composition of claim
 18. 